The amino acids that comprise the building blocks of proteins can be sorted into four groups based on their physical properties. On this page the full names will be used but the commonly used single- and triple-letter codes for the amino acids can be found here.
Hydrophobic amino acids
The largest group contains those amino acids that possess hydrophobic (both aromatic and aliphatic) side chains. The smallest amino acid, glycine, although it formally does not have a side chain is included here since the methylene (CH2) group can be thought of as hydrophobic although is would largely be buried in the polar peptide backbone of the protein. The hydrophobicity of these amino acids makes them important in protein folding and structural stability and also in mediating the binding of the protein to substrates, drugs, other proteins and macromolecular targets within the cell such as DNA/RNA and membranes.
Solvation in the polar aqueous environment of the cell leads to thermodynamic instability due to increased ordering of the waters at the hydrophobic surface and subsequent reduction in the entropy of the system. Bringing together two or more of these hydrophobic side chains forces out the water between them leading to an increase in entropy and a favourable negative free energy change that stabilises the system.
This group also contains the aromatic amino acids phenylalanine, tyrosine and tryptophan which play important structural roles both though the hydrophobic effect and by permitting π-stacking interactions with other aromatic residues and/or aromatic moieties in other molecules bound to the protein.
Polar amino acids
In contrast to the nonpolar hydrophobic amino acids above, the members of this group each possess a polar side chain. The polar moieties that can be seen here are either the simple hydroxyl (OH) group or a carboxamide (CONH2) group at the end of the side chains and these lead the amino acids to favour polar interactions making them more water soluble and also able to become involved in more specific and directional binding interactions than the hydrophobic amino acids. Asparagine and glutamine are derived from aspartic acid and glutamic acid (see below), respectively, by the substitution of NH2 for one of their side chain carboxylic acid oxygens.
The increased polarity compared with the hydrophobic amino acids above means that these uncharged polar side chains are often found on the surface of proteins where they are exposed to the bulk (water) solvent and also play an important part in fine-tuning the relative orientations of the protein and anything bound to it. For this reason these polar amino acid side chains are frequently found in strategic positions within the binding sites for substrates and drugs where they can allow the protein to preferentially bind a specific molecule. Fine-tuning the structure of a new drug can often be made easier if the location of polar side chains in the binding site are known as complementary atom or groups can then be added to the drug molecule to improve its interaction with the site.
In addition to structural and binding roles, the amino acids in this group are capable of participating chemically in reactions mediated by or directly involving the protein. This is facilitated by the polar nature of the bonds between the carbon skeleton of the side chain and the electronegative heteroatoms O and N. These heteroatoms also make these side chains important in the binding of metals to the protein which may themselves play structural and/or chemical roles and may in fact be vital for the correct functioning of the protein.
When compared with amino acids that carry a formal charge (see below) the side chains in this group can be seen to be of intermediate polarity and they are sometimes referred to as ‘indifferent’ amino acids.
Charged amino acids
These amino acids have side chains carrying either a +1 or -1 charge. Histidine is included here because the charged ring nitrogen shown below has a pKa of ~6 meaning that at pH 6 or below it will be mostly protonated and the ring will be charged. Although the overall pH of biological cells is more usually around 7.4 the pH of the local environment that the histidine side chain is exposed to can differ considerably from the bulk and the charged state shown below plays an important role in many processes within proteins. For this reason it is convenient to group histidine with the other charged amino acids. The pKa values of the other side chains in this group are considerably further removed from the background pH 7.4 and for this reason it is safe to class them as permanently charged in a biological setting.
As with the uncharged polar amino acids the polarity of these charged amino acids means that they are frequently found on the surface of proteins where they are exposed to the aqueous environment but also where they can bind to metals and other counterions as well as other proteins and cell structures. An example of the role of charged amino acids in stabilising the binding of proteins to large-scale cell structures is the arginine ‘snorkel’. This is commonly found in proteins that are located within a lipid membrane and consists of arginine side chains that stick up out of the membrane to interact with the negatively charged phosphate groups on the membrane surface (resembling somewhat a diver’s snorkel sticking out of the water).
Histidine is important both for structural reasons and reactivity in proteins. The ring nitrogens are commonly found complexed to metals that can act as ‘anchors’ to hold otherwise flexible parts of a protein in a rigid arrangement and/or act as reactive centres in the catalytic sites of enzymes.
Proline and cysteine
The last two amino acids do not conveniently fit into the groups above and so are put into a separate group that have unusual or perhaps unexpected properties.
Proline is unique in that it contains an aliphatic side chain of three carbons that is covalently linked to both the α-carbon and to the amine nitrogen and forms a ring with the amino acid backbone. For this reason proline is much more rigid than other amino acids and this rigidity is passed on to any protein that it is incorporated into. Proteins from thermophilic organisms have been found to contain high levels of proline which will act to stabilise the protein’s structure at elevated temperatures. Proline is also a key component of collagen, the protein that gives strength to skin and connective tissues in animals.
The thiol (SH) group in cysteine may at first sight make it appear as if it belongs in the polar uncharged group, above. However, the sulfur atom makes cysteine considerably less polar and although it does still take part in metal complexation it is more correctly thought of as a nonpolar side chain. Cysteine also has one more property that sets it aside from the other amino acids and that it the ability to form disulfide (S-S) bonds with other cysteine side chains (see below). This makes cysteine extremely important in stabilising the three-dimensional structures of proteins and also in forming strong covalent links between proteins. A common example of the effect of these inter-protein disulfide links in in the protein β-keratin that is found in animal nails and hair and provides these materials with their rigidity and strength.
Formation of a disulfide bond